PROJECT SUMMARY: A fundamental challenge in the field of neuroscience is understanding the link between environmental signals and the transcriptional response underlying the resulting long term changes in neuronal function. Neurons uniquely require highly dynamic and temporal control of gene activation for processes ranging from memory formation to synapse formation during development. Whether specific genes are ultimately activated is highly dependent on the epigenetic regulation of transcription through the histone proteins that control DNA accessibility and regulate transcription. The importance of this ?histone code? or is becoming increasingly appreciated in neuroscience, from its function in memory storage to its involvement in neurological disorders. My goal is to elucidate the histone code that controls the nervous system with the aim of better understanding the regulation of transcription both in normal neurons and in mental and developmental disorders. The research I propose encompasses all aspects of histone biology including histone binding proteins, histone modifications, and histone variants. I will build on my postdoctoral work by continuing to examine on the role of histone misregulation in neurodevelopmental disorders and the possibility of targeting this to alleviate neuronal dysfunction. I will also continue my investigation into the role of a new discovered histone variant linked to the transcriptional response to synaptic activity. Finally, I will examine the role of histone modifications such as crotonylation that have not yet been examined the context neuronal gene expression but provide the complex transcriptional regulation needed to achieve the varied functions of the nervous system. I will apply the tools and skills I learned during my training to the study of neuroscience. These skills ranging from biochemical approaches to computational and genomics techniques will set me apart from the field and provide me with the background necessary to work at the intersection of epigenetics and neuroscience. As I begin my work as independent investigator, I will be a unique position to apply diverse approaches to reveal new insights into the role of histones in regulating transcription of genes critical for neuronal function. This research will allow for the histone code of gene activation to be applied to information storage in the brain, providing new insights into mechanism underlying neuronal function and the epigenetic causes of neurological disorders.